Atorvastatin is a reductase inhibitor of the enzyme 3-hydroxy-3-methylglutarate-coenzyme A (HMG-CoA) and therefore is a useful anti-hyperlipoproteinemic agent. It has proven to be a highly effective medication for the treatment of disorders such as hyperlipidemia and hypercholesterolemia which are conditions that are known risk factors for arteriosclerosis and coronary heart disease. Atorvastatin is chemically [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrole-1-heptanoic acid and is marketed as its calcium salt under the brand name Lipitor™.
A route to make Atorvastatin 6 is disclosed in U.S. Pat. No. 5,273,995. Depicted in Scheme 1 herein is a sequence of reactions from the process taught in U.S. Pat. No. 5,273,995 which involves the alkylation of aldehyde 1 to form ester 2 followed by transesterification to methylester 3 using sodium methoxide. Methylester 3 is then reacted with the lithium enolate of tert-butylacetate to form the β-ketoester 5, which is then further reacted over a series of steps to form Atorvastatin Calcium 6. If scale-up of the transformation 1 to 5 were contemplated, it would suffer from serious deficiencies. These include:                (a) The aldol reaction has low stereoselectivity (R,S:S,S 84:16) for this case and further recrystallisation steps would be necessary to obtain diastereopure material with a low overall yield (less than 40%).        (b) Silica gel column purification would be necessary to purify the β-hydroxy methylester 3.        (c) The disclosure is silent regarding the recovery of the expensive chiral auxiliary [(S)-1,1,2-triphenyl-1,2-ethanediol, 4].        (d) The initial transesterification step employs the expensive, flammable and corrosive base sodium methoxide and anhydrous conditions.        (e) Sodium methoxide is also a strong base which is expected to lead to detrimental side reactions.        (f) Further, example 3 of the patent requires the addition of the β-hydroxy methylester 3 in absolute THF to the lithium enolate solution “as quickly as possible without allowing the temperature to rise above −40° C.”.        

Recently disclosed in Canadian Patent application 2,460,935 is an improved preparation of hydroxy acid 7 from the aldol product 2 as depicted in Scheme 2. This process requires the establishment of the correct stereochemistry prior to hydrolysis step.

It is therefore an object of this invention to provide processes which overcome deficiencies of the prior art. It is a further object of this invention to provide a facile and commercially viable process to produce atorvastatin calcium 6 in enantiomerically enriched form.
Further and other object of this invention will be realized by those skilled in the art from the following Summary of the Invention and the Examples thereof.